The present invention relates to the field of genes encoding ion channels, and the proteins encoded thereby, and more particularly to genes related to the human Erg gene.
A family of genes that encode potassium ion channel proteins have been identified in and isolated from, various organisms including C, elegans, Drosophila, mouse, rat, and humans. The members of the gene family are classified into subfamilies (eag, elk, and erg) on the basis of sequence similarity. The Eag family is named for the original isolate from Drosophila (ether-a go-go or eag). The Elk family includes genes that encode eag-like potassium ion channels. The Erg family includes eag-related genes.
Typically there is about 40-50% amino acid identity among proteins in the different subfamilies. Within a subfamily, the amino acid identity is about 60-70% even for proteins from different species. The human Erg ion-channel gene (Herg) corresponds to the LQT-2 genetic locus and maps to chromosome 7 q-35-36. Mutations in Herg can cause long-QT (LQT) syndrome, a relatively rare disorder that causes syncope and sudden death due to ventricular arrhythmia. The characteristic increased electrocardiographic Q-T interval evidences delayed repolarization of the cardiac action potential. At a molecular level, the delayed repolarization is linked with abnormal ion channel behavior. The Herg gene, in particular, is shown to be altered or defective in both acquired and inherited forms of LQT syndrome.
Herg ion channels are inwardly rectifying potassium channels. Herg channels have properties consistent with the gating properties of eag, and other, outwardly-rectifying, S4-containing potassium channels, but with the addition of an inactivation mechanism that attenuates potassium efflux during depolarization. It is thought that these properties of Herg channel function are critical to maintaining normal cardiac rhythmicity. The molecular mechanism by which Herg ion channels protect the heart against inappropriate rhythmicity is elucidated in Smith, P. L., et al., "The Inward Rectification Mechanism of the HERG Cardiac Potassium Channel," 379Nature 33 (1996) and in Miller, C. "The Inconstancy of the Human Heart," 379 Nature 767 (1996).
The Herg gene that encodes the Herg potassium ion channel subunits was described by Warmke, J. W. and B. Ganetzky, "A Family of Potassium Channel Genes Related to eag in Drosophila and Mammals," 91 PNAS USA 3438-3442 (1994), incorporated herein by reference. The Herg DNA sequence is found at Genbank Accession Number U04270. A Drosophila erg gene was described by Titus, S.A., et al., "The Drosophila erg K.sup.+ Channel Polypeptide Is Encoded by the Seizure Locus," 17 J. Neuroscience 875-881 (1997) and is reported at Genbank Accession Number U42204. A C. elegans erg gene is found at Accession Numbers U02425 and U02453 of the Genbank database. The two 10 kb pieces of genomic DNA therein disclosed encode amino acid sequences that align respectively to the N- and C-terminal halves of the Drosophila erg polypeptide.
Because of the critical role played by the Herg gene in a well known human disease, and its use in the development of pharmacological therapies, it is important to determine whether additional Herg-like genes exist in humans that could also play an important role in LQT syndrome or in other diseases characteristic of abnormal ion channel function. Herg channels are also an important target for the development of new pharmaceuticals.